Association studies using familial cases: an efficient strategy for identifying low-penetrance disease alleles

Low-penetrance alleles are likely to contribute to inherited susceptibility to many complex traits. Such alleles will rarely generate multiple-case families and are therefore difficult or impossible to identify through genetic linkage analyses. The search for low-penetrance alleles has therefore centred on comparing the frequencies of specific alleles in cases and controls via an association study. With recent improvements in genotyping technology and cost, and the completion of the HapMap Project, the long-predicted era of whole-genome association studies is now upon us, with several large-scale studies underway. Such studies require the simultaneous performance of a large number of statistical tests, with the result that power to detect association is in short supply, particularly if the disease allele is rare. One strategy to increase the power of an association study is to enrich cases for genetic predisposition; for this purpose, studies based on familial cases have attracted considerable interest. Using cancer as an example of a complex trait, we show that this approach greatly increases the power to detect association under a range of modes of inheritance, relative risks, and allele frequencies, but is especially efficient for detection of rare alleles.